CIRCULATORY EFFECTS OF PETHIDINE IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION

863 Gastrin and Pentagastrin Two subjects (A and F) received infusions of gastrin and pentagastrin without glucose (fig. 2). In A the pentagastrin infusion was terminated after 10 minutes because of side-effects. No significant changes in blood-sugar or plasma-insulin occurred in either volunteer. Two further volunteers (G and H) received control infusions of 5% glucose followed by infusion of glucose plus gastrin (fig. 3). In neither individual did the gastrin augment the plasma-insulin response to the infused glucose. Discussion

The administration of glucagon and secretin, in similar amounts, in these experiments provoked comparable rises in the plasma-insulin, although the pattern of the response differed. Glucagon also raised the blood-sugar. From the data of Sokal and Ezdinli (1967) the increment in circulating glucagon levels would have been small. The pancreatic cells of man, as well as the liver cells, are thus very sensitive to small changes in glucagon levels. Together with the demonstration by Samols et al. (1965) that small increases in circulating levels of immunoreactive glucagon follow glucose ingestion, our data provide some circumstantial evidence for a physiological role of glucagon in modifying the insulin response to glucose. For secretin, we have no information on which to base an estimate of the effect of the injected material upon the circulating level. Earlier experiments (Boyns et al. 1966, 1967) suggested that secretin, released endogenously by the intraduodenal infusion of citric acid, had no effect on plasma-insulin, whether or not glucose was administered concomitantly. The report by Dupre et al. (1967) of augmentation of the insulin response to intravenous glucose by intraduodenal infusions of hydrochloric acid seems to be contradictory. However, the difference may lie in the relative quantities of acid used. Although the total dose of 30 mEq. used by Dupre et al. (1967) is compatible with the calculated rate of acid secretion after a meal (Rune 1967), it is likely that much of this acid is ordinarily buffered before reaching the duodenum. In fact, Rune’s (1967) calculations for man were based upon his earlier demonstration in the dog that the rate of pancreatic bicarbonate secretion amounted to only 17% of the gastric acid secretion (Rune and Henriksen 1967). Dupre et al. (1967) demonstrated an augmentation of insulin secretion by cholecystokinin and gastrin, respectively, and this might also be explained by the liberation of gastric acid by these hormones (Celestin 1967) both of which were administered in near maximal amounts. It is, in any case, unlikely that secretin plays any role in the insulin release induced by oral glucose, which has been shown to have no effect upon pancreatic bicarbonate secretion (Sum and Preshaw 1967). It remains a possibility that secretin may augment insulin release after a meal containing protein, for protein ingestion augments the insulin response to oral glucose (Rabinowitz et al. 1966) and protein digests have been shown, in the dog, to stimulate pancreatic bicarbonate secretion (Wang and Grossman 1951). The situation with regard to insulin release after a meal is complex, for, besides the possible direct effect of gastrointestinal hormones upon thecell and the effects of increased circulating levels of aminoacids, there may be an indirect effect of the hormones through an increase in pancreatic and, therefore, islet blood-flow. This possibility has been invoked by Mintz et al. (1967) and clearly deserves further consideration.

We thank Dr. H. J. Graver, Miss Carol Beech, Miss Ruth Elias, Mr. David Jacoby for their help. R. J. J. receives a grant from the Medical Research Council. N. M. C. receives research grants from the Miriam Sacher Charitable Trust and the Tobacco Research Council. Requests for reprints should be addressed to R. J. J. REFERENCES

Boyns, D. R., Jarrett, R. J., Keen, H. (1966) Lancet, i, 409. (1967) Br. med. J. ii, 676. Butterfield, W. J. H., Fry, I. K., Whichelow, M. J. (1960) Guy’s Hosp. Rep. 109, 95. Celestin, L. R. (1967) Nature, Lond. 215, 763. Dupre, J., Curtis, J. D., Beck, J. C. (1967) 6th Congress of the International Diabetes Federation, Stockholm, 1967. Rojas, L., White, J. J., Unger, R. H., Beck, J. C. (1966) Lancet, ii, 26. Elrick, H., Stimmler, L., Hlad, C. J., Arai, Y. (1964) J. clin. Endocr. Metab. 24, 1076. Hoffman, W. S. (1937) J. biol. Chem. 120, 51. McIntyre, N., Holdsworth, C. D., Turner, D. S. (1964) Lancet, ii, 20. Mintz, D. H., Finster, J., Stept, M. (1967) J. clin. Endocr. Metab. 27, 671. Rabinowitz, D., Merimee, T. J., Maffezzoli, R., Burgess, J. A. (1966) Lancet, ii, 454. Rune, S. J. (1967) Clin. Sci. 32, 443. Henriksen, F. W. (1967) Gastroenterology, 52, 930. Samols, E., Marri, G., Marks, V. (1965) Lancet, ii, 415. Tyler, J., Marri, G., Marks, V. (1965) ibid. p. 1257. Sokal, J. E., Ezdinli, E. Z. (1967) J. clin. Invest. 46, 778. Sum, P. T., Preshaw, R. M. (1967) Lancet, ii, 340. Unger, R. H., Ketterer, H., Eisentraut, A., Dupré, J. (1966) ibid. ii, 24. Wang, C. C., Grossman, M. I. (1951) Am. J. Physiol. 164, 527. -

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-

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CIRCULATORY EFFECTS OF PETHIDINE IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION H. A. REES A. L. MUIR M.B., B.Sc. Wales, M.R.C.P.

M.B. Edin., M.R.C.P.E.

SENIOR REGISTRAR

LBCTURER

H. R. MACDONALD Edin., M.R.C.P.E.

D. M. LAWRIE M.B., M.R.C.P.E., M.R.C.P.

M.B.

SENIOR

REGISTRAR*

LECTURER

J. L. BURTON M.B., B.Sc. Manc., M.R.C.P. LECTURER

K. W. DONALD M.A., M.D. Cantab., D.Sc. Birm., F.R.C.P., F.R.C.P.E., F.R.S.E. PROFESSOR OF MEDICINE

UNIVERSITY DEPARTMENT OF

MEDICINE, EDINBURGH 3

ROYAL

INFIRMARY,

observations were made in Summary Circulatory with acute

eight patients

myocardial

infarction after the intravenous administration of 100 mg. pethidine. There seemed to be a biphasic response to the drug, with an initial rise in mean systemic arterial pressure, systemic vascular resistance, and heart-rate, followed, in 10-15 minutes, by a fall in these variables to levels below those in the control period. Because of its circulatory effects, pethidine would not seem to be the ideal drug for the relief of pain in myocardial infarction. Introduction

SINCE Thomas

et

al. (1965) demonstrated the potentially

dangerous hypotensive effects of morphine in patients with acute myocardial infarction, attention has been focused on alternative analgesics. In eight patients, heroin was

found

to

have little effect

on

the cardiovascular system

(Macdonald, Rees, Muir, Lawrie, Burton, and Donald 1967), but in view of the recent increase in the number of heroin addicts in the U.K., many physicians may be reluctant to encourage the drug. Pethidine has been *

Present

more

widespread

suggested

as

an

of this alternative

use

appointment: consultant physician, Royal Infirmary, Huddersfield.

864 TABLE I-PERSONAL AND CLINICAL DETAILS OF PATIENTS

analgesic (British Medical Journal 1966), but its effects in patients with a recent myocardial infarction have not been studied. We report here the results of such an investigation. Patients and Methods Clinical Data

Eight patients were investigated (table I). All had had a myocardial infarction within the previous 48 hours, as judged by the criteria described by the World Health Organisation (1959). Four patients had no complications (nos. 1, 5, 6, and 7), two patients (nos. 3 and 4) were hypertensive, two patients were in pain (nos. 2 and 8), and one of these (no. 8) was hypotensive. All were in sinus rhythm and none had received any drug other than phenindione (’ Dindevan’) within the previous 12 hours. No patient had an oral temperature above 994°F.

Fig. 1-Circulatory effects

of intravenous

Plan of Study The patients were in their own beds in a specially adapted side-room of a general medical ward; all were investigated in the horizontal position with one pillow supporting the head. Control observations were made for 20 minutes. 100 mg. pethidine diluted in 10 ml. saline solution was injected into the right atrium over a 5-minute period, observations being made during this time and for a further 50 minutes in all patients. The plan of study, the techniques used, and the monitoring precautions taken were identical to those described for the heroin study (Macdonald, Rees, Muir, Lawrie, Burton, and Donald 1967). For statistical analysis of the results, Students’ t test was applied to the individual differences between the mean of the control observations and measurements recorded at the 5th, 10th, 20th, 30th, and 50th minutes after the start of injection.

pethidine in eight patients with

acute

myocardial

infarction.

865 Results Clinical Observations After the injection of pethidine, the analgesic effect was adequate in the two patients who had pain. Four of the eight patients (nos. 2, 3, 6, and 7) became drowsy within 10 minutes and slept for short periods throughout the rest of the study period. In these four, no undesirable effects were observed. The other four patients complained of dizziness and nausea, and sweated profusely. In three of the patients (nos. 1, 4, and 5), these unpleasant symptoms gradually disappeared after 20-30 minutes, but the last patient (no. 8) vomited 4 minutes after the injection and the nausea and dizziness persisted until the end of the

study. Circulatory Changes The sequential changes in the circulatory measurements for each patient are shown in fig. 1 and the mean changes for the group of eight patients in fig. 2. Mean aortic pressure.-In seven patients, there was an increase of 2-21 mm. Hg (mean 12 mm. Hg) in mean aortic pressure lasting for 10-15 minutes after the start of injection. In the remaining patient (no. 5), the mean aortic pressure fell at once and at the 10th minute after the start of injection was 22 mm. Hg below the control level. The average increase in pressure at the 10th minute was significant (p < 0-05). By the 20th minute, the mean aortic pressure in all eight patients had fallen below control levels. From the 30th minute until the end of the study, the average decrease of 10 mm. Hg (range 6-20 mm. Hg) was

highly significant (P < 0-001).

Cardiac output.-The changes in cardiac output after the injection of pethidine were variable. In five patients (nos. 1, 2, 3,4, and 7) the cardiac output at all observations between the 5th and 50th minutes after the injection were at or below mean control levels. This fall was greatest from the 10th to the 20th minute and ranged from 0-63 to 0’05 litre per minute per sq. m. in patients 1 and 3, respectively. In patients 8 and 6, the cardiac output increased initially by 0-17 and 0-43 litre per minute per sq. m., but in these two also the observations from the 30th to the 50th minute after the injection were below control levels. In only one patient (no. 5) was the cardiac output in the last 10 minutes of the study period above the mean control value, and then only by 0-13 litre per minute per sq. m. As a result of the variation in individual response, the mean changes for the group were not

statistically significant. Systemic vascular resistance.-The systemic vascular resistance was increased in all patients in the first

TIME - MINS

Fig. 2-The mean circulatory changes in eight patients with myocardial infarction.

10 minutes after injection (p < 005). For the last 30 minutes of the study, the systemic vascular resistance decreased to control levels in two patients (nos. 1 and 7) and below control levels in the other six. Heart-rate and stroke volume.-The heart-rate increased within 5 minutes of the administration of pethidine by an average of nine beats per minute (range 2-24 beats per minute, P < 0-05). The stroke volume at the same time interval decreased by an average of 3-5 ml. per sq. m. (p < 001). Thereafter, both heart-rate and stroke volume tended to return to control levels and did not differ significantly from them. Mean right atrial pressure.-Mean right atrial pressure recordings were not obtained in one patient (no. 7) because of a technical fault. In the other seven, the control levels ranged from 0-10 mm. Hg (mean 3-6 mm. Hg). After pethidine, the changes were small except in two patients: the pressure increased by 6 mm. Hg in patient 4 and decreased by 6 mm. Hg in patient 5. However, variations in the catheter position may have contributed to changes in this measurement and the significance of these findings is difficult to assess. Mean pulmonary arterial pressure.-The mean pulmonary arterial pressure ranged from 12 to 23 mm. Hg (mean 17 mm. Hg) during the control period in the seven

TABLE II-CHANGES IN ARTERIAL OXYGEN AND CARBON-DIOXIDE TENSIONS AND

N.s.

=

Not

acute

significant.

pH

AFTER

100 mg.

PETHIDINE

866

in whom satisfactory measurements could be obtained. There was an average increase of 3 mm. Hg at the 10th minute after pethidine and a subsequent tendency to return to control levels. There was some individual variation, however, and no statistically significant trend was detectable. Calculated oxygen uptake.-The mean oxygen uptake, calculated from the cardiac output and arteriovenous oxygen differences, was 146 ml. per minute per sq. m. during the control period (range 118-186). There was no significant change after pethidine. Arterial blood-gases and pH.- The individual changes in blood-gases and pH are shown in table 11. The mean Pao2 in the control period was 71 mm. Hg (range 48-84 mm. Hg). At the 5th and 10th minute after the start of injection, the mean Pao2 had fallen to 66 mm. Hg (range 47-82 mm. Hg, P < 0-05). Thereafter, although there was some individual variation, the values tended to return towards control levels and did not differ significantly from them. The initial mean Pac02 of 34-5 mm. Hg (range 27-47 mm. Hg) increased to 39-7 mm. Hg at the 5th minute after the start of pethidine injection and remained of the order of 38 mm. Hg until the end of the study period (p < 0-01). The mean pH in the control period was 7-47 (range 7-42-7-52), and decreased significantly at the 5th minute after the start of injection and at all further observations. This change was greatest at 30 minutes when the mean pH was 7-43 (range 7-39-7-52).

patients

previously supposed. They stressed the fact that unpleasant symptoms develop rapidly and usually pass off within an hour. Three of our patients showed this type of response but in one the nausea persisted for more than an

hour.

It would seem, therefore, that pethidine produces more circulatory disturbance and, in this small series, more frequent unpleasant side-effects than heroin, which has previously been shown to provide adequate analgesic and sedation with only slight effects on the cardiovascular

system. We thank the consultant physicians of the Royal Infirmary for allowing us to study their patients; Sister M. G. Mitchell and the nursing staff; Miss J. Barclay, Mrs. C. Simpson, and other members of the technical staff of the department of medicine for their invaluable help; and Mrs. L. Brock for secretarial assistance. Requests for reprints should be addressed to H. A. R. REFERENCES

British Medical Journal (1966) ii, 3.

Dundee, J. W., Clarke, R. S. J., Loan, W. B. (1965) Lancet, ii, 1262. Gallen, B., Prescott, F. (1944) Br. med. J. i, 176. Macdonald, H. R., Rees, H. A., Muir, A. L., Lawrie, D. M., Burton, J. L., Donald, K. W. (1967) Lancet, i, 1070. Prescott, F., Ransom, S. G., Thorp, R. H., Wilson, A. (1949) ibid. i, 340. Sapru, R. P. (1966) PH.D. thesis, University of Edinburgh. Thomas, M., Malmcrona, R., Fillmore, S., Shillingford, J. (1965) Br. Heart J. 27, 863. World Health Organisation (1959) Tech. Rep. Ser. W.H.O. no. 168.

EFFECT OF HEXACHLOROPHENE ON RESIDENT SKIN FLORA OF NEWBORNS

Discussion

Although the precise pharmacological action of pethidine on the cardiovascular system is outside the scope of the limited intravascular techniques used here, it seems that pethidine has a dual action on the circulation in with myocardial infarction. Initially, there is a patients " " stimulatory phase lasting 10-15 minutes during which the mean aortic pressure is increased. This is followed by a gradual decrease in mean aortic pressure, cardiac output, heart-rate, and systemic vascular resistance. The initial increase in mean aortic pressure has been reported in healthy individuals (Prescott et al. 1949) and in obstetric patients (Gallen and Prescott 1944). Sapru (1966) noted a similar change lasting only 1 or 2 minutes after a bolus injection of intravenous morphine. The pressor response in his series of healthy individuals and patients with mitral-valve disease was due to a rate-dependent increase in cardiac output with a decrease in systemic vascular resistance, which he postulated was due to histamine release. In our series, although the heart-rate tended to increase, the cardiac output fell, and the initial rise in pressure was due entirely to an increase in systemic vascular resistance. Although we did not measure pulmonary vascular resistance, it is interesting that in this initial period both pulmonary arterial and right atrial pressures increased

I. SARKANY M.R.C.P. CONSULTANT DERMATOLOGIST

CHRISTINE C. GAYLARDE B.Sc. Lpool RESEARCH ASSISTANT

DEPARTMENT OF

ROYAL FREE

The effect of

The mechanism of this biphasic response to pethidine not clear, but the result is a fluctuation of mean aortic pressure ranging on average from 12 mm. Hg in the initial phase, to -10 mm. Hg in the later stages. While this did not harm any of our patients, it might do so in a case where the safety margin between the maximum work of which the damaged heart is capable and the minimum tissue-perfusion requirement is critically reduced. While the analgesic effects of pethidine were adequate, four of our eight patients experienced dizziness and Dundee et al. (1965) have shown that these nausea. side-effects of the drug are more common than was

the

Summary resident flora ofhexachlorophene the normal skin in 82 on

babies was compared with that produced by washing with soap and water. After washing the babies with hexachlorophene, the numbers of non-pathogenic staphylococci were greatly reduced in the axilla, on the scalp, and in the periumbilical area and there was a less striking reduction in the number of diphtheroids. Streptococci and pathogenic organisms either were few and insufficiently constant for comparison or were absent. These findings support the view that the application of hexachlorophene decreases the number of all bacterial elements on the skin surface. Introduction

slightly. is

DERMATOLOGY, HOSPITAL, GRAY’S INN ROAD, LONDON W.C.1

PREVIOUS investigations of the effect of hexachlorophene skin bacteria have been mainly concerned either with the prevention of pyogenic skin lesions in early infancy (Farquharson et al. 1952, Gezon et al. 1964) or with the reduction in the number of pathogenic staphylococci in infancy (Gillespie et al. 1958). The advantages of washing or not washing the newborn with soap and water, of using antiseptic materials, or of bathing in hexachlorophene have long been debated; and the finding of Farquharson et al. (1952) that hexachlorophene prevented pyogenic infections due to staphylococci seemed to favour the use of hexachlorophene. The effect of hexachlorophene

on